Restless Legs Syndrome (“RLS”, also known as Ekbom Syndrome) is a neurological condition that expresses itself as an overwhelming urge to move the legs, usually caused by uncomfortable or unpleasant sensations in the legs at rest. Movement of the legs temporarily alleviates the discomfort. (Jones et al., Restless Legs Syndrome—A Review, Eur. J. Vasc. Endovasc. Surg., December 1997, 14(6):430-2)
The sensations occur during periods of inactivity, and are thus most intense in the evening and at night. RLS often causes difficulty staying or falling asleep, which leads to feelings of daytime tiredness or fatigue. RLS may cause involuntary jerking of the limbs during sleep and sometimes during wakefulness. Because of the nature of these symptoms, RLS is one of the most prevalent causes of sleep disorders such as sleep disturbance and insomnia. (Fox, G. N., Restless Legs Syndrome, American Family Physician, January 1986, 33(1):147-52)
RLS can occur at any age but increases in frequency as persons grow older. (Thorpy J. Michael. New Paradignms in the treatment of restless legs syndrome. Neurology 2005; 64: S28-S33) It afflicts about 8% of the general population. (see, rls.org/)
At least 80% of RLS patients experience periodic leg movements (PLMs), stereotyped, repetitive flexion movements of the legs that occur approximately every 5-90 seconds when the patient is asleep or lying down resting. (Hening A Wayne et al. An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep 2004, 27: 560-583.) Both the sensations in the limbs and the PLMs can profoundly disrupt sleep (getting to sleep and staying asleep). This can lead to excessive daytime sleepiness as well as depression and anxiety and may have a significant negative impact on quality of life.
Treatment of RLS can be difficult and often requires trying different drugs and dosage regimes. (The Merck Manual, 17th Ed. 1999, 1416) The primary pharmacologic treatment of RLS is principally with two classes of medications: dopaminergic agents and opiate agents. (Restless Legs Syndrome Foundation, Inc. Medical Bulletin, April 2004, pg. 15)
Nearly all patients with RLS show at least an initial positive therapeutic response to dopamine precursor levodopa (L-dopa) (either alone or with a dopa decarboxylase inhibitor like carbidopa) at dosages very low compared with those prescribed in the treatment of Parkinson's disease. (Montplaisir J. et al., Restless Legs Syndrome and Periodic Movements in Sleep: Physiopathology and Treatment with L-dopa, Clin. Neuropharmacol., 1986, 9(5):456-463) This initial response, however, is not universally maintained. The drawback of L-dopa therapy lies in the fact that in many patients its effectiveness tapers off and/or the RLS problem is shifted toward the morning hours (rebound) or the disorder is aggravated with the problem occurring event during the day (augmentation). (Guilleminault C. et al., Dopaminergic Treatment of Restless Legs and Rebound Phenomenon, Neurology, 1993, 43(2):445; and Allen R. P., Augmentation of the Restless Legs Syndrome with Carbidopa/Levodopa, Sleep, 1996, 19(3):205-213)
Dopamine-receptor agonists such as pergolide and pramipexole, known by the trade name Mirapex [available from Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT], provide well-established and effective treatment for RLS. However, they have been reported to cause major side effects. (Dooley M. et al., Pramipexole: A Review of Its Use in the Management of Early and Advanced Parkinson's Disease, Drugs Aging, June 1998, 12(6):495-514; and Silber M. H. et al., Pergolide in the Management of Restless Legs Syndrome: An Extended Study, Sleep, 1997, 20(10):878-882) In fact, all of the dopamine agonists can be used to treat RLS but with a negative aspect in that, usually in the beginning and as a function of the dosage administered, they lead to such side effects as nausea, vomiting, dizziness, hypotension, constipation or insomnia. (Medical Bulletin, infra at pg. 17)
Opiates are effective against RLS as well, although often at relatively high doses. (Walters, A. S. et al., Successful Treatment of the Idiopathic Restless Legs Syndrome in a Randomized Double-Blind Trial of Oxycodone Versus Placebo, Sleep, 1993, 16(4):327-332) However, because of the risk of addiction and progressive tolerance these substances are suitable for therapeutic application to a limited extent at best.
Benzodiazepines such as clonazepam and anticonvulsants such as gabapentin and carbamazepine have also been shown to alleviate the symptoms of RLS. (Medical Bulletin, infra at pg. 19) However, side effects similar to those associated with the treatments described above limit use. Addiction and daytime sedation are problematic with benzodiapenes, which does not prevent movement but only prevents awakening. (Id.) High dosages are required in anticonvulsant treatments. Furthermore, it is thought that anticonvulsants fail to resolve the full spectrum of elements of RLS. (Telstad W. et al., Treatment of the Restless Legs Syndrome with Carbamazepine; A Double Blind Study, Br. Med. J. (Clin. Res. Ed.), 1984, 288(6415):444-446)
Valproate has also shown benefit for RLS, but the side effect of weight gain has limited its acceptance. (Dinesin H. et al., Weight Gain During Treatment With Valproate, Acta. Neurol. Scan., 1984, 70(2):65-69) Clonidine, originally developed as an antihypertensive agent and miotic, has also been examined for its effectiveness in the treatment of RLS. While it was found that soporiferous latency was reduced, it had no effect on the quality of sleep, the frequency of waking up or periodic leg movement during sleep. Given that more efficacious substances are available for monotherapy, clonidine is not currently recommended as an alternative form of therapy except in limited situations. (U.S. Patent Publication No. 2001/0053777, published Dec. 20, 2001)
Therefore, there exists a need for an effective, alternative treatment and related treatment regime options for individuals who are afflicted with RLS. More particularly, there exists a need for treatments that do not induce the unwanted effects observed in modern therapeutics of RLS.